A Platform Protocol to Investigate Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis in Patients With Hematologic Malignancies Undergoing Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

• Ages 18 to 66 years
• All sexes
• No healthy volunteers
• Adult, Older adult

Trial locations and contacts

13 sites in 1 country. Contact the study team or a site near you to ask about taking part.

About this study

Conditions

AML (Acute Myelogenous Leukemia), Acute Lymphoid Leukemia (ALL), Acute Leukemia (Category), MDS (Myelodysplastic Syndrome), CML (Chronic Myelogenous Leukemia), CLL (Chronic Lymphocytic Leukemia)

Being tested

Conditioning Regimen A, Conditioning Regimen B, Conditioning Regimen C, Conditioning Regimen D, Conditioning Regimen E

Keywords

ACCELERATE, ACCEL-001, ACCEL-002

Medical subject headings

Leukemia, Myeloid, Acute, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Anemia, Refractory, with Excess of Blasts, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Leukemia, B-Cell, Leukemia, Myelomonocytic, Chronic, Myeloproliferative Disorders, Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

• Conditioning Regimen ADrug

  Busulfan and fludarabine

  Recommended schedule as below:

  • Days -6 to -3: Busulfan ≥ 9 mg/kg total dose (IV or PO) with pharmacokinetic (PK) monitoring recommended as per institutional practice to achieve a daily area under the curve (AUC) target of 4800-5300 μM*min47 or busulfan plasma exposure units (BPEU) 19.7-21.75 mg x h/L48.
  • Days -6 to -2: Flu 30 mg/m2/day (adjusted for renal function) is administered over a 30-60 minute IV infusion (maximum cumulative dose, 150 mg/m2).

• Conditioning Regimen BDrug

  Fludarabine and TBI The recommended fludarabine plus TBI regimen is the following:

  • Days -7, -6 and -5: Flu (30 mg/m2/day, maximum cumulative dose, 90 mg/m2), IV
  • Days -4 to -1: TBI (150 cGy administered twice daily, 1200 cGy total dose)
  • Radiation sources, dose rates, and shielding follow institutional practice.
  • Although not required, it is recommended that palifermin be used to mitigate the risk of mucosal toxicity with this regimen.

• Conditioning Regimen CDrug

  Fludarabine and busulfan (Flu/Bu)

  The recommended Flu/Bu regimen is the following:

  • Days -6 to -2: Flu (30 mg/m2/day, recommended total dose of 150 mg/m2, but not exceeding 180 mg/m2), IV Busulfan options
  • Days -5 to -4: Busulfan without PK - Busulfan 3.2 mg/kg/day IV or oral equivalent; total dose of 6.4 mg/kg IV or oral equivalent respectively
  • Days -5 to -4: Busulfan with PK - target doses to AUC of 4000 μMol/min or BPEU of 16.43 mg x h/L (total BPEU of 65.72 mg x h/L) or less is allowed.

• Conditioning Regimen DDrug

  Fludarabine and melphalan (Flu/Mel)

  The recommended Flu/Mel regimen is the following:

  • Days -7 to -3: Flu (30 mg/m2/day or 25 mg/m2/day, total dose of 125-150 mg/m2), IV
  • Day -1: Mel (100-140 mg/m2 IV for recipients aged 18-59; dose of melphalan cannot exceed 100mg/m2 if age 60 or older or calculated glomerular filtration rate (GFR) is <60 ml/min), IV

• Conditioning Regimen EDrug

  Fludarabine/cyclophosphamide/total body irradiation (Flu/Cy/TBI)

  The recommended Flu/Cy/TBI regimen is the following:

  • Days -6 to -5: Cy (14.5 mg/kg/day IV, total dose of 29 mg/kg, or single dose 50 mg/kg on Day -6 [Minnesota regimen])
  • Days -6 to -2: Flu (30 mg/m2/day, total dose of 150 mg/m2) IV
  • Day -1: TBI 200 cGy single dose Hydration and Mesna may be administered per institutional standards. For recipients of RIC/NMA AND donors matched at <7/8, consider the addition of TBI 200-300cGy for the Flu/Bu and Flu/Mel regimens to mitigate the risk of primary graft failure.

• Hematopoietic Cell TransplantationProcedure or surgery

  • On Day 0, the donor PBSC graft is infused.
  • Donor PBSC will be collected per NMDP/donor registry policies with a target viable CD34+ cell dose of at least 4 × 106 /kg recipient weight (actual, ideal, or adjusted ideal per institutional practice).
  • Dose of CD34+ cells/kg and CD3 cells/kg infused will be recorded.
  • If the donor PBSC graft is cryopreserved prior to the start of conditioning, follow institutional practices to ensure a sufficient cell dose is available for infusion after thawing.
  • The graft cannot be manipulated ex vivo to deplete T cells.

• PTCy (50 mg/kg D3, D4)Drug

  Cyclophosphamide (50mg/kg ideal body weight (IBW); [if actual body weight (ABW) < IBW, use ABW]) will be given on Day +3 (between 60 and 72 hours after the start of the PBSC infusion) and on Day 4 post HCT (approximately 24 hours after Day +3 cyclophosphamide). Cyclophosphamide will be given as an intravenous (IV) infusion over 1-2 hours (depending on volume), or according to institutional standards. Hydration pre- and post- cyclophosphamide and Mesna administration will be given per institutional standards.

  No systemic immunosuppressive agents are given until at least 24 hours after the completion of the PTCy. This includes corticosteroids as anti-emetics but excludes any drugs listed in section 7.9.1.

  Azoles (e.g., posaconazole or voriconazole) must be delayed from beginning of conditioning through completion of Day 4 PTCy dose to avoid potential drug-drug interactions with cyclophosphamide that could lead to increased toxicity.

• PTCy (25 mg/kg D3, D4)Drug

  Cyclophosphamide (25mg/kg ideal body weight (IBW); [if actual body weight (ABW) < IBW, use ABW]) will be given on Day +3 (between 60 and 72 hours after the start of the PBSC infusion) and on Day 4 post HCT (approximately 24 hours after Day +3 cyclophosphamide). Cyclophosphamide will be given as an intravenous (IV) infusion over 1-2 hours (depending on volume), or according to institutional standards. Hydration pre- and post- cyclophosphamide and Mesna administration will be given per institutional standards.

  No systemic immunosuppressive agents are given until at least 24 hours after the completion of the PTCy. This includes corticosteroids as anti-emetics but excludes any drugs listed in Table 4 and Table 5 in Section 7.1.

  Azoles (e.g., posaconazole or voriconazole) must be delayed from beginning of conditioning through completion of Day 4 PTCy dose to avoid potential drug-drug interactions with cyclophosphamide that could lead to increased toxicity.

• Post-transplant TacrolimusDrug

  Tacrolimus will be given per institutional practices, at a dose of 0.05 mg/kg per os (PO) or an IV dose of 0.03 mg/kg of IBW starting on Day + 5. The dose of tacrolimus may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels per institutional guidelines with a suggested range of 5-12 ng/mL. If subjects are on medications which alter the metabolism of tacrolimus (e.g., concurrent CYP3A4 inhibitors), the initial starting dose and subsequent doses should be altered as per institutional practices. Tacrolimus taper is recommended to be initiated at 100 days post HCT if there is no evidence of active GVHD and ended by Day + 180 post HCT.

• Post-transplant Mycophenolate mofetilDrug

  MMF will be given at a dose of 15 mg/kg 3 times daily (TID) (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1g TID, IV or PO). MMF prophylaxis will start Day + 5 and continue until Day + 35 post-transplant, at which time it should be discontinued (no taper necessary). Study site investigators may modify dose/taper early if clinically indicated for the study subject. Dose rounding may be done per institutional practice.

• Post-transplant AbataceptDrug

  Abatacept will be given at a dose of 10 mg/kg with a maximum of 1000 mg.

• Post-transplant RuxolitinibDrug

  Ruxolitinib will be given at a dose of 5 mg/kg twice daily starting at Day 30 post HCT, provided both the absolute neutrophil count (ANC) is > 1000/μl and platelet count is >30,000/μl.

• Supportive Care: Growth FactorsDrug

  Granulocyte colony-stimulating factor (G-CSF) to accelerate neutrophil recovery should be administered starting at Day +5 with dose, route of administration, formulation, and duration of administration following institutional guidelines. Filgrastim biosimilars are permissible, but granulocyte-macrophage colony-stimulating factors are not permissible.

• Supportive Care: Blood ProductsProcedure or surgery

  Transfusion thresholds for blood product support will be consistent with standard institutional guidelines. All blood products must be irradiated.

• Supportive Care: Infection ProphylaxisOther

  Subjects should receive infection prophylaxis according to institutional guidelines and in accordance with the Center for Disease Control (CDC) guidelines49. Infection prophylaxis will include, but is not limited to, agents or strategies (e.g., polymerase chain reaction [PCR] screening and preemptive therapy) to reduce the risk of bacterial, viral (e.g., adenovirus, CMV, EBV, herpes simplex), opportunistic (e.g. Pneumocystis jirovecii, Toxoplasma gondii) and fungal (yeast and mold) infections.

  Infection risk should assess patient-, pathogen-, and immune-related factors that increase susceptibility to infection. Minimal parameters requiring prophylaxis include but are not limited to neutropenia (ANC≤500/μL), lymphopenia (ALC≤500/μL), and exposure to immunosuppression or GvHD. Use of intravenous immunoglobulin (IVIG) should be considered for total IgG<400 mg/dL during exposure to immunosuppression and/or GvHD.

• Supportive Care: Intravenous immune globulin (IVIG)Other

  Intravenous immune globulin (IVIG) administration will be according to local institutional standard practice for hypogammaglobulinemia but is generally not recommended.

• Supportive Care: Seizure prophylaxisDrug

  Subjects will receive busulfan seizure prophylaxis with levetiracetam, fosphenytoin, or lorazepam per institutional guidelines.

• Supportive Care: Monitoring and management of CRSOther

  The use of HLA-mismatched PBSC has been associated with greater risk of CRS relative to bone marrow. Following the infusion of MMUD PBSC on Day 0, subjects should be monitored daily through Day 14 for the development of CRS. High index of suspicion is urged, particularly in the few days following infusion. Many sites have successfully intervened with tocilizumab in order to avoid severe or prolonged CRS. Supportive care is encouraged for CRS Grades 1-2 and tocilizumab (or alternative) is recommended for CRS grade 3-4 where subject outcome may be impacted (Appendix G - CRS Guidance and Management).

• Supportive Care: Prophylaxis against infectionsOther

  Consider monitoring for EBV reactivation during abatacept treatment and continue for six months following HCT.

  Consider monitoring and prophylaxis for CMV infection/reactivation during abatacept treatment and for six months following HCT.

• Supportive Care: Prophylaxis against infectionsDrug

  For participants receiving ruxolitinib, the recommended maximum dose of fluconazole daily is 200 mg.

• Supportive Care: Lipid elevationsOther

  Assess lipid levels 8-12 weeks from start of therapy with ruxolitinib and treat as needed.

• Study treatment complianceOther

  The administration of study agents must be recorded in the subject's medical chart for verification of study treatment compliance.

• Prohibited Concomitant TherapyOther

  Prophylactic anti-viral cellular therapies and/or co-enrollment on studies using therapies for the prevention of GVHD is prohibited.

  Subjects reported to have received prohibited therapy while on this study will be withdrawn and will not be included in the primary and secondary analyses.

  No concomitant systemic immunosuppressive agents can be administered during PTCy (Day 3 and Day 4). If needed, administer at least 24 hours after completion of Day 4 PTCy.

  It is crucial that no systemic immunosuppressive agents are given until at least 24 hours after completion of the Day +4 dose of PTCy. This includes corticosteroids as anti-emetics but excludes tacrolimus and MMF. Steroid use is permitted as pre-medication prior to start of conditioning but is prohibited from Day 0 through 24 hours post Day 4 PTCy administration.

  If prohibited therapies are administered, these data must be reported in the study EDC on the Concomitant Medications form.

• Permitted Concomitant TherapyOther

  Pre-medication and/or treatment for possible AEs related to PTCy are permitted. Subjects may continue all medications in compliance with local treatment center and local institutional guidelines, except those described in Section 7.9.1. If GVHD or infection occurs, enrollment on a clinical trial to treat infection or GVHD is permissible. At time of relapse, patients are permitted to enroll on a clinical trial or receive disease targeted therapy.

  The following medications/therapies must be reported on the study EDC Concomitant Medications form:

  • Medications taken to treat adverse events that have been reported on the study EDC Adverse Event form.
  • Antimicrobial prophylaxis (viral, bacterial, fungal, parasitic).
  • Antimicrobial pharmaceutical and cellular therapies used to treat grade II-III infections per BMT CTN grading criteria (Appendix D - BMT CTN Infection Grading).
  • Post HCT, primary malignant disease-directed pharmaceutical and cellular therapies.
  • Planned maintenance therapy

• Prohibited Concomitant TherapyOther

  Treatment with any other Investigational Medicinal Product (IMP) is not allowed while on study treatment. An IMP is defined as any medication without any known FDA-approved indications.

  No other investigational drugs for GVHD are allowed.

• Permitted Concomitant TherapyOther

  Premedication and/or treatment for possible adverse events (AE)s related to abatacept are permitted.

• Prohibited Concomitant TherapyOther

  Treatment with any other Investigational Medicinal Product (IMP) is not allowed while on study treatment. An IMP is defined as any medication without any known FDA-approved indications.

  Concomitant use of ruxolitinib with fluconazole doses of greater than 200 mg daily should be avoided.

  No other investigational drugs for GVHD are allowed.

• Permitted Concomitant TherapyOther

  Premedication and/or treatment for possible AEs related to ruxolitinib are permitted.

What is being measured

The primary outcome is the main question the study is designed to answer.

1. Graft-versus-host disease-free, relapse-free survival (GRFS)

   To compare GRFS following transplantation of a PBSC product from a MMUD between standard-of-care PTCy-based GVHD prophylaxis (the control arm) and the combination of reduced-dose PTCy, ruxolitinib, tacrolimus, and MMF.

   Measured: 1 year post-HCT

2. Graft-versus-host disease-free, relapse-free survival (GRFS)

   To compare GRFS following transplantation of a PBSC product from a MMUD between standard-of-care PTCy-based GVHD prophylaxis (the control arm) and the combination of reduced-dose PTCy, abatacept, and tacrolimus.

   Measured: 1 year post-HCT

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1. First posted5 Mar 2025
2. Study start25 Jul 2025
3. Primary completionJun 2028 (estimated)
4. Study completionJun 2028 (estimated)

Resources

• Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
• Other trials for AML (Acute Myelogenous Leukemia)Studies of the same condition, open and under way.
• What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.